Atherosclerosis, the primary cause of heart disease and stroke, is accompanied by endothelial dysfunction, an early event in this chronic disease. Development of atherosclerotic lesions is enhanced by intimal neovascularization, a process driven by the interaction between angiogenic factors and their receptors. Increasing evidence supports the involvement of inflammation and of both innate and adaptive immunity in atherogenesis, raising the prospect of a new immunological approach for the treatment of atherosclerosis. The overall objective of this application is to establish that in hyperlipidemic low density lipoprotein receptor-deficient (LDLr-/-) mice a cytotoxic T lymphocyte (CTL) response elicited by novel DNA vaccines against the murine vascular endothelial growth factor (VEGF) receptor 2, Flk-1, is sufficiently robust to suppress atherosclerosis-related angiogenesis and to prevent disease progression. The hypothesis that atheroprotection can be accomplished by breaking peripheral T cell tolerance to the murine Flk-1 antigen, which is overexpressed in activated/proliferating endothelial cells in developing atherosclerotic plaques will be tested. Aim #1 will verify that oral Flk-1 vaccines can prevent or retard progression of atherosclerotic lesions in LDLr-/- mice. Experiments will analyze T cell responses, inhibition of angiogenesis and the anti-atherosclerotic efficiency of Flk-1-based DNA vaccines with emphasis on changes in disease severity and lesion morphology in immunized mice. Aim #2 is to critically evaluate the effect of the Flk-1 vaccines on pre-existing complex atherosclerotic lesions to determine if established advanced atherosclerotic lesions in LDLr-/- mice can be completely or at least partially regressed via Flk-1 vaccination. This novel approach of targeting atherosclerosis has the potential to reduce the risk of cardiovascular events through long-lasting immune responses. Achievement of this proposal's objectives should lead to the development of highly efficient anti-atherosclerotic therapies that will greatly improve future treatment choices for atherosclerosis.